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Nano-sized membrane bubbles known as extracellular vesicles activate the immune system in mice and seem to render their tumours sensitive to a type of immunotherapy drug called a checkpoint inhibitor. This is according to a new study published in Cancer Immunology Research by researchers at Karolinska Institutet in Sweden.
Treatments for various forms of cancer have improved considerably over recent years thanks to a type of drug called a checkpoint inhibitor, which helps the immune system’s T cells to attack the cancer cells.
However, even though some patients respond extremely well to treatment, a large proportion only see temporary improvement, if any. Scientists are devoting considerable energy to understanding why this is so and to combining checkpoint inhibitors with other therapies in order to increase the cancer survival rate.
A new cancer therapy
Researchers from Karolinska Institutet how show that a form of round nanoparticles called exosomes or extracellular vesicles are a promising path to follow.
“Is seems that the vesicles make the tumour immunologically active so that the checkpoint therapy can gain purchase and start to work,” says the study’s last author Susanne Gabrielsson, professor at the Department of Medicine (Solna), Karolinska Institutet. “These results give support to the further development of extracellular vesicles as a new cancer therapy.”
Extracellular vesicles are sometimes referred to as the body’s messengers. They are membrane-bound nano-scale bubbles that cells can send to each other to exchange information. Vesicles from tumour cells, for instance, can switch off the immune system so that the cancer can spread, while vesicles from immune cells can activate an immune response.

After an intrepid, decade-long search, Johns Hopkins Medicine scientists say they have found a new role for a pair of enzymes that regulate genome function and, when missing or mutated, are linked to diseases such as brain tumors, blood cancers and Kleefstra syndrome — a rare genetic, neurocognitive disorder.
The new findings, published Nov. 21 in Epigenetics & Chromatin, could eventually help scientists understand diseases caused by disruption of these enzymes and develop new treatments for them.
“Developing a better understanding of how enzymes impact the activity of our genomes offers valuable insights into biology and can help researchers design new therapeutic approaches for disease,” says Sean Taverna, Ph.D., associate professor of pharmacology and molecular sciences at the Johns Hopkins University School of Medicine.
The search began more than a decade ago, when Taverna was looking for factors that influence DNA activity in Tetrahymena thermophila — a one-celled, fresh water dwelling organism. During the original study, the research team found a previously unknown signal that the single-celled creature uses to “mark” genes it has turned off.
The location of the mark is on histone proteins, which act as spools that tightly wind DNA, often turning off genes and protecting DNA from damage. If Tetrahymena are not able to add the marks — a process called methylation, which adds chemical tags to a part of histones called H3K23 — the DNA becomes damaged and the cells grow poorly.
In a follow up study published in 2016, Taverna found that the H3K23 location is conserved between Tetrahymena and mammals, including humans. However, the enzymes that control how the chemical tags are placed on H3K23 differ between the species.

People suffering from blood cancer often have a weak immune system, putting them at higher risk of falling seriously ill with COVID-19. Some cancer therapies, moreover, result in these patients forming few or no antibodies against SARS-CoV-2 after COVID-19 vaccination. However, vaccination can also activate so-called T cells, which are responsible particularly for the long-term immune response.
A team led by physicians Dr. Andrea Keppler-Hafkemeyer and Dr. Christine Greil from the Medical Center-University of Freiburgand virologist Prof. Oliver T. Keppler from LMU Munich has now characterized in detail the course over several months of the immune response of patients with blood cancer who had received a total of three vaccinations against COVID-19. The results allow inferences to be made about the protection that vaccination gives these patients against serious illness from SARS-CoV2.
Strong T cell response to COVID-19 vaccination
The study focused on patients with two kinds of blood cancer: B-cell lymphoma and multiple myeloma. “Our results show that almost all study participants had a strong T cell response to COVID-19 vaccination,” explains Dr. Andrea Keppler-Hafkemeyer. “This could be one reason why breakthrough infections turned out to be mild to moderately severe even in study participants who had been unable to form any specific antibodies after vaccination because of their therapy,” adds Dr. Christine Greil. The co-principal investigators and lead authors regularly look after blood cancer patients in the Department of Medicine I at the Medical Center — University of Freiburg.
The research group led by Prof. Oliver T. Keppler is specialized not only in analyzing the concentration of antibodies after vaccination, but also their quality. This depends particularly on the strength of the bonds between antibodies and the viral spike protein. In addition, the ability of antibodies to neutralize different SARS-CoV-2 variants in cell cultures plays a major role. As the next step, therefore, the scientists compared the quantity and quality of antibodies and T cell responses to the spike protein among blood cancer patients and healthy study participants after two and three COVID-19 vaccinations.
High-quality antibodies against different SARS-CoV-2 variants
The study revealed that patients who can form antibodies tend to produce antibodies of particularly high quality. After their second vaccination, they are already able to neutralize and thus deactivate different SARS-CoV-2 variants. This ability is considerably more pronounced in this patient cohort than in vaccinated healthy people.
“COVID-19 vaccination can generate very broad antiviral immunity — including highly potent neutralizing antibodies — in patients with various types of blood cancer. Consequently, multiple vaccine doses can be recommended for patients with B-cell lymphoma or multiple myeloma without interrupting therapy,” summarizes Prof. Oliver T. Keppler.
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A phase I clinical trial of PAC-1, a drug that spurs programmed cell death in cancer cells, found only minor side effects in patients with end-stage cancers. The drug stalled the growth of tumors in the five people in the trial with neuroendocrine cancers and reduced tumor size in two of those patients. It also showed some therapeutic activity against sarcomas, scientists and clinicians report in the British Journal of Cancer.
The drug was first identified and developed as an anti-cancer agent by scientists at the University of Illinois Urbana-Champaign.
The findings from the clinical trial are noteworthy because the drug was tested in a small number of patients with advanced disease, said study clinical director Dr. Arkadiusz Dudek, an oncologist with the HealthPartners Cancer Center at Regions Hospital in St. Paul, Minnesota, and at Mayo Clinic in Rochester, Minnesota. Phase I clinical trials are designed to test whether a new drug compound has worrisome side effects or toxicities in human patients, Dudek said. But scientists also can look for early evidence of therapeutic benefits. The trial enrolled cancer patients with advanced disease who had run out of other treatment options.
“We had patients with colon cancer, breast cancer, pancreatic cancer, adenocarcinoma, melanoma and others,” he said.
The clinical trial — and another testing PAC-1 against brain cancer — involves patients and clinicians at three institutions: Regions Hospital, the University of Illinois Chicago and Johns Hopkins University.
Phase I clinical trials track side effects in patients who first are given very low doses of the compound being tested. If the drug is well tolerated and causes no discernible toxicities over the course of a month, the dose is incrementally increased. This process can take several months before a potentially therapeutic dose is given, said Dr. Oana Danciu, a medical oncologist and associate director for clinical research at the University of Illinois Cancer Center in Chicago, who led the clinical trial.

Researchers from Indiana University School of Medicine have discovered a molecular “clamping” mechanism within a male-specific protein-DNA complex whose mutation causes sex reversal: children with XY chromosomes but female bodies, a condition called Swyer Syndrome. The clamp exploits a water molecule bridging the male factor (designated SRY) and DNA control sites at the tenuous beginnings of male development.
The study focuses on the subtle substitution of a conserved aromatic residue in SRY (tyrosine) by a closely related aromatic residue (phenylalanine). The clinical mutation, shared by a fertile XY father and his sterile XY daughter, positions the embryonic male switch at the borderline of genetic function. The two aromatic rings are seemingly interchangeable in the structure of the protein, but differ in their ability to anchor a bridging water molecule in the protein-DNA complex.
“Loss of a single atom in SRY, an oxygen atom in a critical tyrosine, impairs the robustness of male development,” said Michael Weiss, MD, PhD, chair of the Department of Biochemistry and Molecular Biology. “Normally, the father has XY chromosomes and the daughter has XX chromosomes but in some families, the daughters can have XY chromosomes because there is a mutation in SRY. Sex chromosomes can degenerate over evolutionary time scales, leading to new upstream switches being recruited as male-determining pathways grow backwards. Such initial steps can be tenuous in biochemical terms.”
In the study, researchers focused on position 72 in the DNA-binding domain of SRY, which was not previously considered of special interest. However, the researchers discovered that tyrosine at this position enables operation of a water-mediated kinetic clamp, extending the lifetime of the protein-DNA complex. This mechanism is conserved in all mammalian SRY factors and is broadly observed in a related family of switch factors in multicellular (and some unicellular) animals. The latter family, designated “SOX” (SRY-related HMG box) is fundamental to patterning and development in metazoans.
Researchers published two recent papers about their work in Frontiers in Endocrinology. The first describes their findings related to focusing on box 72, and the second describes how the water-mediated clamp mechanism works. Weiss said they call it a “humpty-dumpty” model because of accelerated disassembly of the male-determining protein-DNA complex in the absence of the water-mediated clamp.
“Because the normal and mutant version of SRY are so similar in standard experimental assays,” said Joseph D. Racca, PhD, Assistant Research Professor in the Department of Biochemistry and Molecular Biology and first author of the new study. “Uncovering the water-mediated mechanism took several years. Critical insight was provided by molecular dynamics (MD) simulations of boundary water molecules in this system.”
“In the MD simulations a distinctive water molecule is anchored by the tyrosine as a bridge to the DNA: this special site of hydration is occupied for thousands of picoseconds, and then it will leave,” Weiss said. “But then another water molecule in the bulk solvent will almost immediately hop in its place, restoring the bridge.”
The subtle change from tyrosine to phenylalanine alters such hydration, a perturbation that propagates from position 72 predicted to destabilize successive protein-DNA contacts in the tail of the domain. Detachment of the tail would hasten dissociation of the protein-DNA complex and presumably male-specific gene-regulatory assemblies at target genes.
XY female children with differences in sexual differentiation due to Swyer Syndrome lack functional ovaries and are at risk for rare forms of early-onset gonadal cancer. Recognition of this syndrome is important allowing surgical removal of the gonads before cancer begins. The affected woman otherwise has a normal uterus and birth canal, and so they may bear children following in vitro fertilization of a donated egg.
Weiss said analogous mutations can occur in SOX genes, causing a variety of birth defects or diseases.
“Swyer mutations provide clues to help us understand a broad range of SOX diseases and may give rise to much improved protocols for different areas of medicine, such as regenerative medicine or cancer,” Weiss said. “This discovery thus goes way beyond sex determination because SRY is a prototype switch.”
In addition to Weiss, other study authors from IU include Yen-Shan Chen, PhD, Joseph Racca, PhD, Deepak Chatterjee, PhD, Ratan Rai, PhD, Yanwu Yang, PhD and Millie Georgiadis, PhD. Elisha Haas, PhD of Bar Ilan University in Israel was also a coauthor.

Researchers have discovered a new mode of vertical mother-to-infant microbiome transmission, where microbes in the maternal gut shared genes with microbes in the infant gut during the perinatal period starting immediately before birth and extending thought the first few weeks after birth. This horizontal gene transfer allowed maternal microbial strains to influence the functional capacity of the infant microbiome, in the absence of persistent transmission of the microbial strains themselves. Such a large-scale integrative analysis, presented December 22 in the journal Cell, provides a series of high-resolution snapshots of gut colonization dynamics that influence infant development both before and after birth.
“This is the first study to describe the transfer of mobile genetic elements between maternal and infant microbiomes,” says senior study author Ramnik Xavier of the Broad Institute of MIT and Harvard. “Our study also, for the first time, integrated gut microbiome and metabolomic profiles from both mothers and infants and discovered links between gut metabolites, bacteria and breastmilk substrates. This investigation represents a unique perspective into the co-development of infant gut microbiomes and metabolomes under the influence of known maternal and dietary factors.”
Gut bacteria promote the maturation of the immune system in part through the production of microbial metabolites. The development of the infant gut microbiome follows predictable patterns, starting with transmission of microbes from the mother at birth. In addition to immune system maturation, microbial metabolites also influence early cognitive development. The perinatal period represents a critical window for cognitive and immune system development, promoted by maternal and infant gut microbiota and their metabolites. Nevertheless, the co-development of microbiomes and metabolomes during the perinatal period and the determinants of this process are not well understood.
To address this knowledge gap, Xavier and his colleagues tracked the co-development of microbiomes and metabolomes from late pregnancy to one year of age using longitudinal multi-omics data from a cohort of 70 mother-infant dyads. They discovered large-scale mother-to-infant interspecies transfer of mobile genetic elements, frequently involving genes associated with diet-related adaptations. Infant gut metabolomes were less diverse than maternal metabolomes but featured hundreds of unique metabolites and microbe-metabolite associations not detected in mothers. Metabolomes and serum cytokine signatures of infants who received regular, but not extensively hydrolyzed, formula were distinct from those of exclusively breastfed infants.
“The infant gut harbored thousands of unique metabolites, many of which were likely modified from breastmilk substrates by gut bacteria,” says Tommi Vatanen, co-first author on the study along with Karolina Jabbar, both of the Broad Institute of MIT and Harvard. “Many of these metabolites likely impact immune system and cognitive development.”
Pregnancy was associated with an increase in steroid compounds, including gonadal hormone derivatives and intermediates of bile acid biosynthesis, several of which were independently linked to impaired glucose tolerance. Although infant gut metabolomes were less diverse than maternal metabolomes, the researchers detected more than 2,500 infant-unique metabolomic features. Moreover, they identified numerous infant-specific associations of bacterial species and fecal metabolites, including neurotransmitters and immune modulators.
“We were surprised to find that maternal gut bacteria that were rarely observed in infants contributed to the infant gut microbiome structure,” says Xavier “We also found evidence that prophages — dormant bacteriophages, or viruses that reside on bacterial genomes — contribute to the exchange of mobile genetic elements between maternal and infant microbiomes.”
The authors say that the maternal microbiome may shape the infant gut microbiome through horizontal gene transfer, apart from classical vertical transmission of strains and species. Moreover, the identification of distinctive metabolomic profiles and microbe-metabolite interactions in the infant gut constitutes a platform for further study of microbial contributions to infant development.
One study limitation was that the researchers did not consider changes in diet and lifestyle between pregnancy and the postpartum period, which may have affected microbiome and metabolome alterations. In future studies, they plan to further explore linkages between bacteria and metabolites and investigate strain-specific bacterial metabolic output using isolated bacteria in vitro.
“Taken together, our integrative analysis expands the concept of vertical transmission of the gut microbiome and provides new insights into the development of maternal and infant microbiomes and metabolomes during late pregnancy and early life,” Xavier says.
This work was funded by the National Institutes of Health, the Juvenile Diabetes Research Foundation, the Center for Microbiome Informatics and Therapeutics, and the Wallenberg Foundations. Xavier is co-founder of Jnana Therapeutics and Celsius Therapeutics, Board Director at MoonLake Immunotherapeutics, and consultant to Nestlé; these organizations had no role in the study. All other authors declare no competing interests.
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Scientists used patient stem cells and 3D bioprinting to produce eye tissue that will advance understanding of the mechanisms of blinding diseases. The research team from the National Eye Institute (NEI), part of the National Institutes of Health, printed a combination of cells that form the outer blood-retina barrier — eye tissue that supports the retina’s light-sensing photoreceptors. The technique provides a theoretically unlimited supply of patient-derived tissue to study degenerative retinal diseases such as age-related macular degeneration (AMD).
“We know that AMD starts in the outer blood-retina barrier,” said Kapil Bharti, Ph.D., who heads the NEI Section on Ocular and Stem Cell Translational Research. “However, mechanisms of AMD initiation and progression to advanced dry and wet stages remain poorly understood due to the lack of physiologically relevant human models.”
The outer blood-retina barrier consists of the retinal pigment epithelium (RPE), separated by Bruch’s membrane from the blood-vessel rich choriocapillaris. Bruch’s membrane regulates the exchange of nutrients and waste between the choriocapillaris and the RPE. In AMD, lipoprotein deposits called drusen form outside Bruch’s membrane, impeding its function. Over time, the RPE break down leading to photoreceptor degeneration and vision loss.
Bharti and colleagues combined three immature choroidal cell types in a hydrogel: pericytes and endothelial cells, which are key components of capillaries; and fibroblasts, which give tissues structure. The scientists then printed the gel on a biodegradable scaffold. Within days, the cells began to mature into a dense capillary network.
On day nine, the scientists seeded retinal pigment epithelial cells on the flip side of the scaffold. The printed tissue reached full maturity on day 42. Tissue analyses and genetic and functional testing showed that the printed tissue looked and behaved similarly to native outer blood-retina barrier. Under induced stress, printed tissue exhibited patterns of early AMD such as drusen deposits underneath the RPE and progression to late dry stage AMD, where tissue degradation was observed. Low oxygen induced wet AMD-like appearance, with hyperproliferation of choroidal vessels that migrated into the sub-RPE zone. Anti-VEGF drugs, used to treat AMD suppressed this vessel overgrowth and migration and restored tissue morphology.
“By printing cells, we’re facilitating the exchange of cellular cues that are necessary for normal outer blood-retina barrier anatomy,” said Bharti. “For example, presence of RPE cells induces gene expression changes in fibroblasts that contribute to the formation of Bruch’s membrane — something that was suggested many years ago but wasn’t proven until our model.”
Among the technical challenges that Bharti’s team addressed were generating a suitable biodegradable scaffold and achieving a consistent printing pattern through the development of a temperature-sensitive hydrogel that achieved distinct rows when cold but that dissolved when the gel warmed. Good row consistency enabled a more precise system of quantifying tissue structures. They also optimized the cell mixture ratio of pericytes, endothelial cells, and fibroblasts.
Co-author Marc Ferrer, Ph.D., director of the 3D Tissue Bioprinting Laboratory at NIH’s National Center for Advancing Translational Sciences, and his team provided expertise for the biofabrication of the outer blood-retina barrier tissues “in-a-well,” along with analytical measurements to enable drug screening.
“Our collaborative efforts have resulted in very relevant retina tissue models of degenerative eye diseases,” Ferrer said. “Such tissue models have many potential uses in translational applications, including therapeutics development.”
Bharti and collaborators are using printed blood-retina barrier models to study AMD, and they are experimenting with adding additional cell types to the printing process, such as immune cells, to better recapitulate native tissue.
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Materials provided by NIH/National Eye Institute. Note: Content may be edited for style and length.

In a new study evaluating the Mediterranean diet and adverse pregnancy outcomes, investigators from the Smidt Heart Institute at Cedars-Sinai found that women who conceived while adhering to the anti-inflammatory diet had a significantly lower risk of developing preeclampsia during pregnancy.
The study, published today in the peer-reviewed journal JAMA Network Open, also evaluated the association between the Mediterranean diet and other adverse pregnancy outcomes, including gestational diabetes and hypertension, preterm birth, delivery of a small-for-gestational-age infant, and stillbirth.
“This multicenter, population-based study validates that a healthier eating pattern is associated with a lower risk of adverse pregnancy outcomes, the most exciting being a 28% lower risk for preeclampsia,” said Natalie Bello, MD, MPH, senior and corresponding author of the study and director of Hypertension Research in the Smidt Heart Institute. “Importantly, this connection between the Mediterranean diet and lower risk of adverse pregnancy outcomes was seen in a geographically, racially and ethnically diverse population.”
Bello also notes that researchers found the association was stronger in women who are traditionally considered to be of advanced maternal age, those 35 or older.
Preeclampsia is a serious blood pressure condition that develops during pregnancy and puts stress on the mother’s heart. Left untreated, the condition can cause serious complications like weakened kidney and liver function and decreased blood supply to the fetus.
In addition to preeclampsia, the risk of gestational diabetes also decreased in women who more closely followed the heart-healthy diet.

The risk of firearm death in the U.S. is on the rise: in 2020, firearms became the leading cause of death for children, adolescents and young adults. Yet the risk is far from even — young men in some U.S. zip codes face disproportionately higher risks of firearm-related injuries and deaths.
To better understand the magnitude of the gun violence crisis and put it in perspective, researchers at Brown University and the University of Pennsylvania compared the risk of firearm-related death for young adult men living in the most violent areas in four major U.S. cities with the risks of combat death and injury faced by U.S. military personnel who served in Afghanistan and Iraq during active periods of war.
The results were mixed: The study, published in JAMA Network Open, found that young men from zip codes with the most firearm violence in Chicago and Philadelphia faced a notably higher risk of firearm-related death than U.S. military personnel deployed to wartime service in Afghanistan and Iraq. But the opposite was true in two other cities: The most violent areas in New York and Los Angeles were associated with much less risk for young men than those in the two wars.
In all zip codes studied, risks were overwhelmingly borne by young men from minority racial and ethnic groups, the study found.
“These results are an urgent wake-up call for understanding, appreciating and responding to the risks and attendant traumas faced by this demographic of young men,” said Brandon del Pozo, an assistant professor of medicine (research) at Brown’s Warren Alpert Medical School and an assistant professor of health services, policy and practice (research) at the University’s School of Public Health.
Del Pozo conducts research at the intersection of public health, public safety and justice, focusing on substance use, the overdose crisis, and violence. His recently released book, “The Police and the State: Security, Social Cooperation, and the Public Good,” is based on his academic research as well as his 23 years of experience as a police officer in New York City and as chief of police of Burlington, Vermont.

Using a specialized MRI sensor, MIT researchers have shown that they can detect light deep within tissues such as the brain.
Imaging light in deep tissues is extremely difficult because as light travels into tissue, much of it is either absorbed or scattered. The MIT team overcame that obstacle by designing a sensor that converts light into a magnetic signal that can be detected by MRI (magnetic resonance imaging).
This type of sensor could be used to map light emitted by optical fibers implanted in the brain, such as the fibers used to stimulate neurons during optogenetic experiments. With further development, it could also prove useful for monitoring patients who receive light-based therapies for cancer, the researchers say.
“We can image the distribution of light in tissue, and that’s important because people who use light to stimulate tissue or to measure from tissue often don’t quite know where the light is going, where they’re stimulating, or where the light is coming from. Our tool can be used to address those unknowns,” says Alan Jasanoff, an MIT professor of biological engineering, brain and cognitive sciences, and nuclear science and engineering.
Jasanoff, who is also an associate investigator at MIT’s McGovern Institute for Brain Research, is the senior author of the study, which appears today in Nature Biomedical Engineering. Jacob Simon PhD ’21 and MIT postdoc Miriam Schwalm are the paper’s lead authors, and Johannes Morstein and Dirk Trauner of New York University are also authors of the paper.
A light-sensitive probe
Scientists have been using light to study living cells for hundreds of years, dating back to the late 1500s, when the light microscope was invented. This kind of microscopy allows researchers to peer inside cells and thin slices of tissue, but not deep inside an organism.